There is compelling evidence that abnormally elevated intracellular free calcium is one of the early events in the chain of reactions leading to neuronal damage under pathological conditions that range from acute neural injuries, such as stroke, to more chronic indications, such as Alzheimer's disease. High intracellular free calcium can cause mitochondrial injury and activate various types of enzymes, such as proteases, nitric oxide synthases and endonucleases. These calcium-induced/activated cellular responses are believed to mediate cytotoxicity that eventually leads to neuronal death.
There are two major mechanisms that can cause elevation of intracellular free calcium: 1) calcium influx from extracellular space through calcium and non-selective cation channels on the cell membrane, and 2) calcium release from intracellular stores, such as endoplasmic reticulum and mitochondria, through specialized receptor-channel complex, such as ryanodine receptor channels. These two mechanisms often interact. For example, calcium entered the cell through ion channels on the cell membrane can trigger more calcium release from intracellular stores. This calcium-induced calcium release (CICR) has been demonstrated to contribute to neuronal damage under pathological conditions.
Glutamate is the major excitatory neurotransmitter in the brain, including the retina. Its biological action is mediated by a variety of glutamate receptors, including the NMDA receptor that is an ionotropic receptor coupled with a non-selective cation channel that has high calcium permeability. Under pathological conditions, glutamate becomes a neurotoxin that causes neuronal damage in both acute neural injuries, such as stroke, to more chronic indications, such as Alzheimer's disease. This glutamate excitotoxicity is mediated, to a large extent, by the NMDA receptor because of its high calcium permeability. Over stimulation of the NMDA receptor resulting from either excessive release or reduced reuptake of glutamate causes intracellular calcium overload that can eventually lead to neuronal death. Calcium entering the neuron through NMDA channels can stimulate more calcium release from intracellular stores via specialized ligand-activated channels, such as ryanodine channels. This calcium-induced calcium release amplifies cellular response triggered by NMDA receptor activation and has been shown to contribute to excitotoxicity under pathological conditions.
Glaucoma is a neurodegenerative retinal disease characterized by progressive death of retinal ganglion cells (RGCs, the output neuron of the retina), which leads to progressive vision loss and eventually to complete blindness. Glaucoma can be classified into two major categories: hypertensive and normotensive. The underlying causes for glaucoma are still not well understood. The initial insults for the two types of glaucoma are likely different. High intraocular pressure is believed to be a major risk factor for the hypertensive glaucoma whereas the vascular abnormality is though to play a significant role in initiation and progression of the normotensive glaucoma. Despite the difference in initial insults, progressive death of RGCs appears to be a common feature shared by both types of glaucoma.
There is increasing evidence that glutamate-induced excitotoxicity plays a significant role in the pathology of glaucoma. It has been demonstrated that glutamate concentration in vitreous humor from the glaucoma patients is significantly higher than that of normal subjects and the vitreal glutamate concentration increases with the years with glaucoma. It has also been shown that the NMDA receptor antagonist, memantine, ameliorates RGC loss in glaucomatous monkeys, suggesting that the NMDA receptor mediates, at least in part, glutamate-induced damage to RGCs in glaucoma.
Diabetic retinopathy is another chronic degenerative retinal disease that leads progressive vision loss. Recent studies provide evidence that ischemia and glutamate excitotoxicity contribute to neural injury in diabetic retinopathy. This suggests that calcium release from intracellular stores is likely involved in the pathology of diabetic retinopathy.
Thus, it is evident that there is an unmet need for agents that have neuroprotective effects that can stop or retard the progressive damage to CNS neurons resulting from abnormally elevated intracellular free calcium caused by various noxious provocations.
Dantrolene, a skeletal muscle relaxant, has been found to be an antagonist of the ryanodine receptor-channel complex (See Biochemistry 2001, 40, 531-542). Dantrolene blocks calcium release from ryanodine channels when it binds to the receptor.
Dantrolene is 1-[[5-(p-Nitrophenyl)furfurylidene]amino]hydantoin.
